PROJECTSUMMARY Wearefacingagrowingcrisisofagreaternumberofseniorslivingwithadeclineincognitivefunctionasa commonconsequenceofaging.Onceanimpairmenthasreachedalevelofclinicalsignificance,treatment optionsarelimited.Weproposetoexamineage-relateddifferencesintraitandstateautonomiccontrolofheart rateandtheirrelationtocognitiveperformancehumansandrats.Whilecognitivechangesmaybemaskedby compensatoryefforts,autonomicmeasuresmaybemorerevealingoftheunderlyingage-relatedchangesinthe neuralsubstratesandneurochemistryofaginganditsclinicalcourse.Wewillexaminetheseautonomic regulationofheartrate,itsrelationtoandmodulationbycognitiveperformance,asaperipheralproxyofearly centralalterationofthecholinergicbasalforebrain(BF),aprogenitorofsystem-wideneuroanatomicaland neurochemicalchangesrelatedtoaging.Tounderstandtheunderlyingneuralmechanisticbasesofthese autonomicindices,wewillapplyacross-speciesapproach,includinghumanfunctionalneuroimagingaswellas nonhumanneurochemicalexaminations.SpecificAim1willexaminewhetherage-relateddifferencesin cognitivecontrolareassociatedwithalteredautonomicregulationoftheheart.Approach:Wewillemploy across-sectionalexaminationofinhibitorycognitivecontroltasks,whichwehaveshowntodependonthe cholinergicBFinrats,inadiversesampleofmaleandfemaleyoung,middle-aged,andolderadults,examining howcognitiveperformancerelatestoautonomicparasympatheticinfluencesontheheart,reflectedinvagally- mediatedheartratevariability(phasic,beat-to-beatheartratevariability).SpecificAim2willexaminethe specificroleoftheBF,anditsafferentnetworks,inconnectingage-relateddifferencesincognitive controlandautonomicregulationoftheheart.Approach:Wewillemploymulti-echofMRItoacquirehigh SNRsignalfromBFnucleiandautonomicphasicparasympatheticinfluencesonheart,andtheirrelationto neurocognitiveaging,whilecharacterizingandcontrollingforage-relateddifferencesincerebralbloodflowwith arterialspinlabelling.SpecificAim3willtestthehypothesizedparallelcausalcontributionsofBF cholinergicneuronstocentralcognitiveregulationandperipheralautonomicregulationoftheheart. Approach:Usingcholinergicimmunotoxiclesions,aratmodelofcognitiveagingwillassessthecausalroleof theBFtocognitivecontrolandparasympatheticautonomicregulationofheartrate(vmHRV)inmaleandfemale young,middle-aged,andolderrats.Revealingperipheralautonomicaspectsofage-relateddifferencesinbrain integrityandcognitivestatuswouldadvanceourunderstandingofnormativeandpotentiallypathological neurochemicalchangesinaging.Itwillfurtheradvancetheuseofanoninvasive,low-costperipheralbiomarker foridentifyingthosewhomayprogresstomildneurocognitivedisorder(mNCD).Suchareadilyadministered screenforearlymNCDcouldbetteraffordearlydetection,monitoring,andpotentialinterventionbeforethe onsetofmNCDandpotentialconversiontoAlzheimer?sDisease.